Investigation of signalling from the microenvironment in metastasis of invasive lobular breast cancer

Closing date: 07/03/2025

MB-PhD Project: Investigation ofsignallingfrom the microenvironmentin metastasis ofinvasive lobular breast cancer

Lead Supervisors: Professor Robert Clarke
Co-Supervisors:
Dr Sacha Howell, Dr Bruno Simoes and Dr Hannah Harrison

Applications Deadline: Friday 7th March 2025

Project Keywords: Breast cancer, Cytokines, Metastasis
Research Opportunity: Intercalated PhD, leading to the award of PhD and MBChB

Project Outline

This project focuses on lobular breast cancer (LBC), a less-studied subtype of breast cancer constituting about 15% of diagnoses. LBC is characterised by mutations or deletions in E-cadherin (CDH1), distinguishing it from other types.

This breast cancer variant is primarily ER+HER2-, categorising it under the luminal A subtype, which qualifies patients for endocrine and CDK4/6inhibitor therapies. While these treatments are effective and lower recurrence rates, late recurrences (10-20 years) occur in 20% of LBC patients.

LBC has different metastasis patterns compared to ductal breast cancers as it commonly spreads to bones, intestines, skin, and notably the peritoneum, where ascites form. The project will investigate the IL6/STAT3 and IGF1/AKT signalling pathways, known to promote cancer stem cell (CSC) activity, proliferation and resistance to endocrine and CDK4/6 therapies, indicating an important potential role in LBC

Preliminary data reveal that IL6 levels in the ascitic fluid of metastatic LBC patients are significantly elevated and stimulate growth and CSC activity. The study hypothesises that IL6 and IGF1 secreted from mesothelial, cancer-associated fibroblast and immune cells in peritoneal as cites activate STAT3 and AKT signalling, contributing to therapy resistance and tumour proliferation and metastasis.

Specific aims include characterising IL6 and IGF1 signalling in LBC cells within the peritoneal microenvironment, testing such pathways in patient-derived LBC samples, and employing inhibitors to assess impacts on cancer behaviour in 3D culture and in vivo preclinical models.

Expected outcomes include enhanced knowledge of LBC behaviours and the identification of new therapeutic targets for treatment. This research aims to elucidate mechanisms of metastatic progression and resistance in lobular breast cancer.

About Prof. Robert Clarke (project Lead Supervisor)

Rob is Professor of Breast Biology and Director of the Manchester Breast Centre, based at the Oglesby Cancer Research Building.  Undergraduate BSc studies were in Biology at the University of Sussex and Université Grenoble Alpes.  Following two and half years as a Research Assistant with Chris Potten at the Paterson Institute for Cancer Research, Rob studied the control of proliferation in the normal and neoplastic human mammary gland for his PhD at The University of Manchester (1995).  Post-doctoral training was with Dr Liz Anderson in the Clinical Research Department of The Christie, Manchester, and in 2001, Rob returned to The University of Manchester as a Cancer Research UK Research Fellow in Cancer Biology. Rob was appointed as a lecturer and Breast Cancer Now Research Fellow from 2006-2011, a Senior Lecturer from 2009 and a Reader in Breast Biology from 2014-2018.

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